The invention features methods for regulating vascular properties by controlling endothelial cell behavior using optogenetic reagents and light, and uses thereof. In certain embodiments, the invention features methods for regulating the permeability of the blood-brain barrier for delivery of therapeutics to the brain and for regulating vascular tone and vascular growth.
Drugs injected via intravascular (IV) injections provide an optimal pathway for the non-invasive delivery of therapeutics to the brain. The primary impediment to optimal IV use is the blood-brain barrier (BBB). This barrier is crucial for normal brain function, preventing cross-talk between blood elements and the brain. In medical practice, the BBB is an obstacle and prevents almost all beneficial drugs from entering the brain.
Given the importance of BBB opening for drug delivery, several approaches have been attempted to open or circumvent the BBB. Agents such as mannitol, which creates a hyper-osmotic condition, or adenosine, are non-specific in space—they open the entire BBB—and at best have minimal open duration of tens of minutes and often compromise the BBB for hours. A second ‘global’ approach has been drug synthesis to mimic elements that naturally pass the BBB. These ‘trojan horses’ emulate small molecules to use their BBB ferrying systems, or engage large molecule receptor mediated transfer. This approach has significant promise, but suffers from the basic challenge of spatial and temporal precision endemic to any existing IV method, and it requires molecular engineering for each agent (alterations that could impact drug efficacy).
Currently, a single established method claims to provide non-invasive spatio-temporal precision in BBB opening—localized ultrasound pulsing of micro-bubbles injected IV. The mechanisms underlying this breach of the BBB are not known, but are believed to occur through mechanical aggravation of the endothelial cell (EC) layer that is the primary constituent of the BBB. This method is undesirable for several reasons. First, each opening of the BBB is technically complex—magnetic resonance imaging (MRI) is required to guide focusing of ultrasound to obtain spatial specificity. Second, the ‘transient’ opening achieved by this technique compromises the BBB for at least 3-5 hours. Third, the method works through an aphysiological mechanical BBB rupture, which is unlikely to allow multiple uses without creating chronic local reactivity or damage.
Thus there is a need for non-invasive and simple methods for the regulation of vascular permeability, especially in the BBB, with high spatial and temporal precision for delivery of therapeutics.
Several maladies result from failures in proper vascular tone, arterial diameter or improper vascular growth (angiogenesis). Thus there is also a need for non-invasive methods for controlling vascular tone, arterial diameter and vascular growth.